We have previously demonstrated the effective synthesis and use of enzymatically stable oligonucleotide ethyltriesters and methylphosphonates in selectively inhibiting protein synthesis in cultured cells. Consistent with published results we find relatively high external concentrations required for effective protein synthesis inhibition due in part to limited cell penetration of some derivatives. We propose to develop the use of highly- soluble, cell penetrating amphiphilic oligonucleotide conjugates which initial experiments show to be 10 time more effective than non-conjugated oligomers. The goal is produce effective antisense oligonucleotides with significant antiviral activity. In Phase I we will synthesize and purify polyethylene glycol conjugates of normal and methylphosphonate DNA and compare their ability to selectively inhibit hemoglobin synthesis in cultured mouse cells. In Phase II we intend to construct and test the optimized conjugates for their ability to inhibit the growth of HIV in cultured cells. We will then extend this work to animal toxicity and pharmacologic studies to bring these compounds to the IND stage for testing in humans.